College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China.
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
J Virol. 2024 Mar 19;98(3):e0115723. doi: 10.1128/jvi.01157-23. Epub 2024 Feb 2.
Pet golden hamsters were first identified being infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant of concern (VOC) and transmitted the virus back to humans in Hong Kong in January 2022. Here, we studied the binding of two hamster (golden hamster and Chinese hamster) angiotensin-converting enzyme 2 (ACE2) proteins to the spike protein receptor-binding domains (RBDs) of SARS-CoV-2 prototype and eight variants, including alpha, beta, gamma, delta, and four omicron sub-variants (BA.1, BA.2, BA.3, and BA.4/BA.5). We found that the two hamster ACE2s present slightly lower affinity for the RBDs of all nine SARS-CoV-2 viruses tested than human ACE2 (hACE2). Furthermore, the similar infectivity to host cells expressing hamster ACE2s and hACE2 was confirmed with the nine pseudotyped SARS-CoV-2 viruses. Additionally, we determined two cryo-electron microscopy (EM) complex structures of golden hamster ACE2 (ghACE2)/delta RBD and ghACE2/omicron BA.3 RBD. The residues Q34 and N82, which exist in many rodent ACE2s, are responsible for the lower binding affinity of ghACE2 compared to hACE2. These findings suggest that all SARS-CoV-2 VOCs may infect hamsters, highlighting the necessity of further surveillance of SARS-CoV-2 in these animals.IMPORTANCESARS-CoV-2 can infect many domestic animals, including hamsters. There is an urgent need to understand the binding mechanism of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants to hamster receptors. Herein, we showed that two hamster angiotensin-converting enzyme 2s (ACE2s) (golden hamster ACE2 and Chinese hamster ACE2) can bind to the spike protein receptor-binding domains (RBDs) of SARS-CoV-2 prototype and eight variants and that pseudotyped SARS-CoV-2 viruses can infect hamster ACE2-expressing cells. The binding pattern of golden hamster ACE2 to SARS-CoV-2 RBDs is similar to that of Chinese hamster ACE2. The two hamster ACE2s present slightly lower affinity for the RBDs of all nine SARS-CoV-2 viruses tested than human ACE2. We solved the cryo-electron microscopy (EM) structures of golden hamster ACE2 in complex with delta RBD and omicron BA.3 RBD and found that residues Q34 and N82 are responsible for the lower binding affinity of ghACE2 compared to hACE2. Our work provides valuable information for understanding the cross-species transmission mechanism of SARS-CoV-2.
宠物金黄仓鼠首先被确定感染了严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）delta 变体关切变异株（VOC），并于 2022 年 1 月在香港将病毒传播回人类。在这里，我们研究了两种仓鼠（金黄仓鼠和中国仓鼠）血管紧张素转换酶 2（ACE2）蛋白与 SARS-CoV-2 原型和八种变体的刺突蛋白受体结合域（RBD）的结合，包括 alpha、beta、gamma、delta 和四种 omicron 亚变体（BA.1、BA.2、BA.3 和 BA.4/BA.5）。我们发现，两种仓鼠 ACE2 与所有九种 SARS-CoV-2 病毒的 RBD 的亲和力略低于人类 ACE2（hACE2）。此外，用九种假型 SARS-CoV-2 病毒证实了对表达仓鼠 ACE2 和 hACE2 的宿主细胞的相似感染性。此外，我们确定了金黄仓鼠 ACE2（ghACE2）/delta RBD 和 ghACE2/omicron BA.3 RBD 的两个低温电子显微镜（EM）复合物结构。存在于许多啮齿动物 ACE2 中的残基 Q34 和 N82 负责 ghACE2 与 hACE2 相比的结合亲和力较低。这些发现表明，所有 SARS-CoV-2 VOC 都可能感染仓鼠，这凸显了在这些动物中进一步监测 SARS-CoV-2 的必要性。重要性 SARS-CoV-2 可以感染许多家畜，包括仓鼠。迫切需要了解 SARS-CoV-2 变体与仓鼠受体的结合机制。在此，我们表明两种仓鼠血管紧张素转换酶 2（ACE2）（金黄仓鼠 ACE2 和中国仓鼠 ACE2）可以与 SARS-CoV-2 原型和八种变体的刺突蛋白受体结合域（RBD）结合，并且假型 SARS-CoV-2 病毒可以感染表达仓鼠 ACE2 的细胞。金黄仓鼠 ACE2 与 SARS-CoV-2 RBD 的结合模式与中国仓鼠 ACE2 相似。两种仓鼠 ACE2 与所有九种 SARS-CoV-2 病毒的 RBD 的亲和力略低于人类 ACE2。我们解决了与 delta RBD 和 omicron BA.3 RBD 复合的金黄仓鼠 ACE2 的低温电子显微镜（EM）结构，并发现残基 Q34 和 N82 负责 ghACE2 与 hACE2 相比的结合亲和力较低。我们的工作为了解 SARS-CoV-2 的跨物种传播机制提供了有价值的信息。
